Major depressive illness is a devastating disorder with broad socioeconomic effects. Although pharmacological treatments for depression have been available for over 40 years, these drugs are not always effective and they require weeks or even months of treatment. The acute actions of most antidepressants occur via inhibition of the reuptake or breakdown of norepinephrine (NE) and serotonin (5-HT), but the mechanisms underlying the therapeutic actions of chronic antidepressant treatment (ADT) remain largely unknown. The requirement for long-term ADT has lead to the hypothesis that cellular and molecular adaptations to elevated levels of NE and 5-HT mediate the therapeutic response. Studies from our laboratory have demonstrated that the cAMP-CREB (cAMP response element binding protein) signal transduction cascade and a target of this pathway, BDNF (brain derived neurotrophic factor), contribute to the action of ADT. We have demonstrated that different classes of antidepressants, including NE and 5-HT selective reuptake inhibitors, increase CREB and BDNF expression in limbic structures, and that CREB and BDNF are sufficient to produce an ADT-response in behavioral models. This work has resulted in the neurotrophic hypothesis of depression, a leading theory in the field, and one of the aims of this proposal is to test this hypothesis by determining if CREB and BDNF are necessary, as well as sufficient for an ADT-response. These studies also indicate that activation of cAMP-CREB or BDNF signaling would produce an ADT response. This is supported by studies demonstrating that drugs that activate the cAMP-CREB cascade, by inhibition of the cAMP phosphodiesterase type 4 (PDE4), produces an ADT-response in rodent models and in humans. Another major aim of this proposal is to identify which of the PDE4 subtype(s) underlies the ADT response. A related aim is to determine if activation of the BDNF signaling pathway also produces an ADT response, and to investigate proteins in this pathway, particularly protein phosphatases, that could be targeted for drug development. Because there are no selective drugs for these targets, we will use complimentary approaches, including null mutant mice that we have engineered or obtained and viral vectors for local expression of wild type or dominant negative genes. These studies will further characterize the mechanisms underlying the action of ADT and identify novel drug targets for the development of faster acting and more efficacious medications.